TY - JOUR
T1 - Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes
AU - Loviglio, M. N.
AU - Leleu, M.
AU - Männik, K.
AU - Passeggeri, M.
AU - Giannuzzi, G.
AU - van der Werf, I.
AU - Waszak, S. M.
AU - Zazhytska, M.
AU - Roberts-Caldeira, I.
AU - Gheldof, N.
AU - Migliavacca, E.
AU - Alfaiz, A. A.
AU - Hippolyte, L.
AU - Maillard, A. M.
AU - van Dijck, A.
AU - Kooy, R. F.
AU - Sanlaville, D.
AU - Rosenfeld, J. A.
AU - Shaffer, L. G.
AU - Andrieux, J.
AU - Marshall, C.
AU - Scherer, S. W.
AU - Shen, Y.
AU - Gusella, J. F.
AU - Thorsteinsdottir, U.
AU - Thorleifsson, G.
AU - Dermitzakis, E. T.
AU - Deplancke, B.
AU - Beckmann, J. S.
AU - Rougemont, J.
AU - Jacquemont, S.
AU - Reymond, A.
AU - AUTHOR GROUP
AU - Loviglio, Maria Nicla
AU - Männik, Katrin
AU - van der Werf, Ilse
AU - Giannuzzi, Giuliana
AU - Zazhytska, Marianna
AU - Gheldof, Nele
AU - Migliavacca, Eugenia
AU - Alfaiz, Ali A.
AU - Roberts-Caldeira, Inês
AU - Hippolyte, Loyse
AU - Maillard, Anne M.
AU - Ferrarini, Alessandra
AU - Butschi, Florence Niel
AU - Conrad, Bernard
AU - Vansenne, Fleur
AU - Maas, Saskia M.
AU - Barge-Schaapveld, Daniela Q. C. M.
AU - Knegt, Alida C.
PY - 2017
Y1 - 2017
N2 - Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes
AB - Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes
U2 - https://doi.org/10.1038/mp.2016.84
DO - https://doi.org/10.1038/mp.2016.84
M3 - Article
C2 - 27240531
SN - 1359-4184
VL - 22
SP - 836
EP - 849
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 6
ER -